Nicotine pouch

ABSTRACT

The disclosure provides chewable nicotine formulations comprising an orally-acceptable nicotine salt, an orally-acceptable alcohol, flavor components, and an orally-acceptable binder in a water-permeable, water-insoluble pouch, together with methods of making and using the same.

FIELD

This disclosure relates to chewable pouch products comprising nicotinein free base and salt form, together with methods of making and usingthe same.

BACKGROUND

The health hazards of smoking are well-established. Products which candeliver nicotine via the oral mucosa rather than via the lungs includesnuff, snus, chewing tobacco, nicotine chewing gums, and oral pouchescomprising nicotine. These products face challenges in manufacturing,shelf stability, efficient nicotine delivery, and consumer acceptance.Nicotine is readily oxidized, so to enhance shelf stability, nicotinebase may be stabilized in a polymer or gum matrix or provided in saltform. Nicotine free base is believed to be better absorbed through theoral mucosa than nicotine salts, so products which provide nicotine insalt form may further comprise pH-adjusting agents to raise the oral pHupon use, thereby releasing the free base. High pH products may haveundesirable bitter or soapy flavors, and/or poor mouthfeel, whileproducts where nicotine is polymer-stabilized may release nicotinerelatively slowly and inefficiently. The disadvantages of these chewableproducts may make them unappealing to users as an alternative tosmoking, even though products that deliver nicotine by smoking maypresent greater danger to the heart and lungs than chewable products.

There is a need for chewable nicotine delivery products, which releasenicotine quickly and efficiently, have good flavor and mouthfeel, andwhich are stable for long-term storage.

SUMMARY

The disclosure provides a chewable nicotine product, comprising nicotinebase, nicotine salt, flavor, and binder in a water-permeable,water-insoluble pouch, wherein nicotine and flavor are released when thepouch is chewed, and wherein the product provides good nicotine release,flavor, mouthfeel, and shelf-stability.

For example, in one embodiment, the disclosure provides a chewablenicotine formulation comprising nicotine, an orally-acceptable nicotinesalt, an orally-acceptable alcohol, flavor components, and binder in awater-permeable, water-insoluble pouch.

In another embodiment, the disclosure provides a method for making apouch comprising nicotine, nicotine acid addition salt, propyleneglycol, flavor, and binder, wherein the nicotine acid addition salt isformulated in nonaqueous conditions, using propylene glycol as solvent,and products made thereby.

In another embodiment, the disclosure provides a method of deliveringnicotine, for example a method of nicotine replacement therapy,comprising administering the above-described chewable pouch to a subjectin need thereof.

Further areas of applicability of the present disclosure will becomeapparent from the detailed description provided hereinafter. It shouldbe understood that the detailed description and specific examples, whileindicating certain preferred embodiments of the disclosure, are intendedfor purposes of illustration only and are not intended to limit thescope of the disclosure.

DETAILED DESCRIPTION

The formulations of the disclosure are non-aqueous formulations,comprising nicotine and orally-acceptable acid to form a nicotine acidaddition salt in an orally-acceptable alcohol solvent (e.g., propyleneglycol), together with flavor and binder, in a water-permeable,water-insoluble pouch. Alcohols, such as propylene glycol, have a muchlower dielectric constant than water, so the nicotine andorally-acceptable acid dissolved in the alcohol do not produce ions tothe same extent as they would in water, which has unpredictable effectson salt formation, relative to salt formation in aqueous solution. It isfound that the nicotine acid addition salt provided thereby is stablerelative to nicotine in entirely free base form, but also provides abetter mouth feel and nicotine delivery than a nicotine salt formed inaqueous solution.

In a first embodiment, the disclosure provides a chewable nicotineformulation comprising nicotine, an orally-acceptable nicotine salt, anorally-acceptable alcohol, flavor components, and an orally-acceptablebinder in a water-permeable, water-insoluble pouch (Formulation 1). Forexample, the disclosure provides the following formulations:

1.1. Formulation 1 wherein the orally-acceptable nicotine salt isselected from nicotine hydrochloride, nicotine dihydrochloride, nicotinemonotartrate, nicotine bitartrate, nicotine sulphate, nicotine zincchloride monohydrate, nicotine pyruvate, nicotine phosphate, nicotinesalicylate, nicotine malate, nicotine carbonate, nicotine bicarbonate,nicotine acetate, nicotine citrate, nicotine folate, nicotine fumarate,nicotine lactate, and nicotine benzoate.

1.2. Any foregoing formulation wherein the orally-acceptable nicotinesalt is a salt of an orally-acceptable organic acid.

1.3. Any foregoing formulation wherein the orally-acceptable nicotinesalt is a salt of an orally-acceptable monoprotic organic acid.

1.4. Any foregoing formulation wherein the orally-acceptable nicotinesalt is nicotine benzoate.

1.5. Any foregoing formulation wherein the molar ratio between nicotinefree base and orally-acceptable nicotine salt is 1:1 to 1:10.

1.6. Any foregoing formulation wherein the molar ratio between nicotinefree base and nicotine acid addition salt is about 1:2.

1.7. Any foregoing formulation wherein the formulation comprises anorally-acceptable acid, e.g., selected from hydrochloric acid, tartaricacid, pyruvic acid, phosphoric acid, salicylic acid, malic acid,carbonic acid, acetic acid, citric acid, tartaric acid, folic acid,fumaric acid, lactic acid, and benzoic acids; e.g., benzoic acid.

1.8. Any foregoing formulation wherein the orally-acceptable alcohol ispropylene glycol.

1.9. Any foregoing formulation wherein the binder is selected frompolysaccharides, polyols, sugars, natural fibers, microcrystallinecellulose, cellulose and cellulose derivatives, and mixtures thereof.

1.10. Any foregoing formulation wherein the binder is a hydroscopic butinsoluble material.

1.11. Any foregoing formulation wherein the binder comprisesmicrocrystalline cellulose.

1.12. Any foregoing formulation wherein the water-permeable, waterinsoluble pouch is made of a semi-permeable material which substantiallyprevents the binder from leaving the bag but permits saliva and thereindissolved components from the powder in the pouch to freely pass throughsaid material.

1.13. Any foregoing formulation wherein the water-permeable, waterinsoluble pouch is made from one or more polymers or fibers safe fororal use, e.g., selected from polypropylene, low density polyethylene,polyethylene terephthalate, polyurethane, polyvinyl acetate, polyvinylalcohol, polystyrene, poly(ethylene-vinyl acetate), rayon, silk, cotton,polyester, cellulosic materials (e.g., hydroxypropyl cellulose), andcombinations thereof.

1.14. Any foregoing formulation further comprising one or moreadditional components selected from antioxidants, emulsifiers,preservatives, and solvents.

1.15. Any foregoing formulation further comprising a neutral,orally-acceptable mineral salt, e.g., selected from sodium chloride,potassium chloride, and mixtures thereof, e.g., comprising potassiumchloride.

1.16. Any foregoing formulation which is substantially free of any basicingredient other than nicotine.

1.17. Any foregoing formulation which is substantially free of water.

1.18. Any foregoing formulation which is made under substantiallywater-free conditions.

1.19. Any foregoing formulation, wherein the contents of thewater-permeable, water-insoluble pouch have a pH of less than 7, e.g.,pH 5.5 to pH 6.9, e.g., about pH 6.5, when measured in a 10% slurry inwater.

1.20. Any foregoing formulation, wherein the ratio by weight of (i)binder and (if present) neutral orally-acceptable mineral salt, e.g.,potassium chloride, to (ii) nicotine, orally-acceptable nicotine salt,orally-acceptable alcohol, and flavor, is from 70:30 from 50:50, e.g.,65:35 to 55:45, e.g. about 60:40.

1.21. Any foregoing formulation wherein the orally-acceptable nicotinesalt is nicotine benzoate, the orally-acceptable alcohol is propyleneglycol, and the orally-acceptable binder is microcrystalline cellulose.

1.22. Any foregoing formulation wherein the contents of thewater-permeable, water-insoluble pouch consist of nicotine, nicotinebenzoate, potassium chloride, propylene glycol, flavor, and binder.

1.23. Any foregoing formulation wherein the contents of thewater-permeable, water-insoluble pouch consist of nicotine, nicotinebenzoate, potassium chloride, propylene glycol, flavor, andmicrocrystalline cellulose.

1.24. Any foregoing formulation wherein the flavor components are pHneutral.

1.25. Any foregoing formulation wherein the flavor components comprisesone or more flavors selected from mint oil, menthol, watermelon,blueberry, pomegranate, strawberry, blueberry, dragonfruit, and cucumberflavors.

1.26. Any foregoing formulation wherein the flavor components comprisemint oil and/or menthol.

1.27. Any foregoing formulation wherein the nicotine comprises syntheticnicotine. 1.28. Any foregoing formulation wherein the nicotine comprisesnicotine from tobacco. 1.29. Any foregoing formulation wherein thenicotine has an (R):(S) isomeric ratio of greater than 1.

1.30. Any foregoing formulation wherein the contents of thewater-permeable, water-insoluble pouch are in dry powder form.

1.31. Any foregoing formulation comprising 1%-9%, e.g. 2-5%, e.g.,2.5-3.5%, of nicotine and orally-acceptable nicotine salts, by weight ofthe contents of the water-permeable, water-insoluble pouch.

1.32. Any foregoing formulation comprising 4-20%, e.g., 5%-15%, e.g.,about 5%, or about 10%, or about 15%, of orally-acceptable alcohol, e.g.propylene glycol, by weight of the contents of the water-permeable,water-insoluble pouch.

1.33. Any foregoing formulation comprising 50%-70%, e.g. 55%-60%, ofbinder, e.g., microcrystalline cellulose, by weight of the contents ofthe water-permeable, water-insoluble pouch.

1.34. Any foregoing formulation comprising 0.5%-2%, e.g., 1%-1.5%, oforally-acceptable mineral salt, e.g. potassium chloride, by weight ofthe contents of the water-permeable, water-insoluble pouch.

1.35. Any foregoing formulation wherein the contents of thewater-permeable, water-insoluble pouch comprise:

-   -   Nicotine: 1% to 6%, e.g. 1% to 3%, e.g., 2%    -   Benzoic acid: 0.5% to 3%, e.g., 0.5% to 1.5%, e.g., 1%    -   Propylene glycol: 5% to 20%    -   Flavor: 20% to 35%    -   Microcrystalline cellulose: 55% to 60%    -   Potassium chloride: 1% to 1.5%    -   wherein all amounts are by weight of the contents of the pouch,    -   wherein the nicotine and benzoic acid may be in free or salt        form or mixtures thereof, and    -   wherein the weight of the nicotine is calculated as the free        base equivalent and the weight of the benzoic acid is calculated        as the free acid equivalent, irrespective of the actual        proportions of nicotine and benzoic acid in free or salt form.

1.36. Formulation 1.35 wherein the weight percent of the solidcomponents comprising microcrystalline cellulose and potassium fluorideis 55% to 65%, e.g., about 60%; and the weight percent of the liquidcomponents comprising propylene glycol, nicotine, benzoic acid andflavor is 35% to 45%, e.g., about 40%.

1.37. Formulation 1.35 or 1.36 wherein the weight ratio of nicotine tobenzoic acid is 1:1 to 3:1, e.g., about 2:1.

1.38. Formulation 1.35, 1.36 or 1.37 wherein the molar ratio of nicotineto benzoic acid is 3:1 to 1:3, e.g., from 2:1 to 1:1, e.g., is about3:2.

1.39. Any foregoing formulation wherein each pouch contains a dose of 1mg to 15 mg nicotine, e.g., 5-10 mg nicotine, e.g., about 8 mg nicotine,wherein the weight of the nicotine is calculated as the free baseequivalent, irrespective of whether the nicotine is in free base or saltform.

1.40. Any foregoing formulation wherein the weight of the contents ofthe pouch is from 0.2 g to 1 g, e.g. from 0.3 g to 0.5 g, e.g., about0.4 g.

1.41. Any foregoing formulation when made according to any of Methods 1,et seq.

1.42. Any foregoing formulation for use in a method of deliveringnicotine to a subject, e.g. a person in need of nicotine replacementtherapy.

1.43. Any foregoing formulation wherein the formulation has a shelf lifeof at least 6 months, e.g. at temperatures up to 40° C.

1.44. Any foregoing formulation wherein the formulation has a pH of lessthan 7, e.g., pH 5.5 to pH 6.9, e.g., about pH 6.5, when measured in a10% slurry in water, and exhibits improved stability, mouth feel, and/orflavor relative to a product having a pH of at least 8 when measured ina 10% slurry in water.

In another embodiment, the disclosure provides a method (Method 1) ofmaking a chewable nicotine formulation, e.g., according to any ofFormulation 1 above, comprising the steps of

-   -   a) dissolving nicotine and an orally-acceptable acid in a        non-aqueous orally-acceptable solvent,    -   b) adding flavor components,    -   c) mixing with solid orally-acceptable binder and optionally a        salt, and    -   d) filling a water-permeable, water-insoluble pouch with the        mixture thus obtained.        For example, Method 1 comprises

1.1. Method 1 wherein the orally-acceptable acid is selected fromhydrochloric acid, tartaric acid, pyruvic acid, phosphoric acid,salicylic acid, malic acid, carbonic acid, acetic acid, citric acid,tartaric acid, folic acid, fumaric acid, lactic acid, and benzoic acids.

1.2. Any foregoing method wherein the orally-acceptable acid is anorganic acid.

1.3. Any foregoing method wherein the orally-acceptable acid is amonoprotic organic acid.

1.4. Any foregoing method wherein the orally-acceptable acid is benzoicacid.

1.5. Any foregoing method wherein the molar ratio between nicotine andorally-acceptable acid in step a) is from 3:1 to 1:3, e.g., from 2:1 to1:1.

1.6. Any foregoing method wherein the molar ratio between nicotine andorally-acceptable acid in step a) is about 3:2.

1.7. Any foregoing method wherein the orally acceptable acid is benzoicacid, and the weight ratio of weight ratio of nicotine to benzoic acidin step a) is 1:1 to 3:1, e.g., about 2:1.

1.8. Any foregoing method wherein the nonaqueous solvent comprisespropylene glycol, e.g. wherein the nonaqueous solvent is propyleneglycol.

1.9. Any foregoing method wherein the nonaqueous solvent is heated tofacilitate dissolution of the nicotine and the orally-acceptable acid.

1.10. Any foregoing method wherein the binder is selected frompolysaccharides, polyols, sugars, natural fibers, microcrystallinecellulose, cellulose and cellulose derivatives, and mixtures thereof.

1.11. Any foregoing method wherein the binder is a hydroscopic butinsoluble material.

1.12. Any foregoing method wherein the binder comprises microcrystallinecellulose.

1.13. Any foregoing method wherein the water-permeable, water insolublepouch is made of a semi-permeable material which substantially preventsthe binder from leaving the bag but permits saliva and therein dissolvedcomponents from the powder in the pouch to freely pass through saidmaterial.

1.14. Any foregoing method wherein the water-permeable, water insolublepouch is made from one or more polymers or fibers safe for oral use,e.g., selected from polypropylene, low density polyethylene,polyethylene terephthalate, polyurethane, polyvinyl acetate, polyvinylalcohol, polystyrene, poly(ethylene-vinyl acetate), rayon, silk, cotton,polyester, cellulosic materials (e.g., hydroxypropyl cellulose), andcombinations thereof.

1.15. Any foregoing method further comprising adding one or moreadditional components selected from antioxidants, emulsifiers,preservatives, and solvents.

1.16. Any foregoing method further comprising adding to the binder aneutral alkali salt, e.g., selected from sodium chloride, potassiumchloride, and mixtures thereof, e.g., potassium chloride.

1.17. Any foregoing method wherein no basic ingredient is added otherthan nicotine.

1.18. Any foregoing method wherein all steps are carried out undersubstantially water-free conditions.

1.19. Any foregoing method wherein the product of step b) has anapparent pH of 5 to less than 7, e.g. about 5.5-6.5, when measured usinga pH-sensitive glass electrode concentrically surrounded by a referenceelectrode filled with reference electrolyte, which measures the H⁺ ionconcentration of the solution.

1.20. Any foregoing method, wherein the product of step c) has a pH ofless than 7, e.g., pH 5.5 to pH 6.9, e.g., about pH 6.5, in a 10% slurryin water.

1.21. Any foregoing method, wherein the ratio by weight of (i) binderand (if present) neutral alkali salt, e.g., potassium chloride, to (ii)nicotine, nicotine benzoate, propylene glycol, and flavor in the productof step c) is from 70:30 from 50:50, e.g., 65:35 to 55:45, e.g. about60:40.

1.22. Any foregoing method wherein the product of step c) consists ofnicotine, nicotine benzoate, potassium chloride, propylene glycol,flavor, and binder.

1.23. Any foregoing method wherein the product of step c) consists ofnicotine, nicotine benzoate, potassium chloride, propylene glycol,flavor, and microcrystalline cellulose.

1.24. Any foregoing method wherein the flavor components are pH neutral.

1.25. Any foregoing method wherein the flavor components comprise one ormore flavors selected from mint oil, menthol, watermelon, blueberry,pomegranate, strawberry, blueberry, dragonfruit, and cucumber flavors.

1.26. Any foregoing method wherein the flavor components comprise mintoil and/or menthol.

1.27. Any foregoing method wherein the nicotine comprises syntheticnicotine. 1.28. Any foregoing method wherein the nicotine comprisesnicotine from tobacco.

1.29. Any foregoing method wherein the nicotine has an (R):(S) isomericratio of greater than 1.

1.30. Any foregoing method wherein the product of step c) in dry powderform.

1.31. Any foregoing method wherein the product of step c) comprises2-5%, e.g., 2.5-3.5%, of nicotine and nicotine salts, by weight.

1.32. Any foregoing method wherein the product of step c) comprises4-20%, e.g., 5%-15%, e.g., about 5%, or about 10%, or about 15%, ofpropylene glycol, by weight.

1.33. Any foregoing method wherein the product of step c) comprises50%-70%, e.g. 55%-60%, of microcrystalline cellulose, by weight.

1.34. Any foregoing method wherein the product of step c) comprises0.5%-2%, e.g., 1%-1.5%, of potassium chloride, by weight.

1.35. Any foregoing method wherein:

-   -   in step a), the amount of nicotine is 1% to 3%, e.g., 2%, the        orally-acceptable acid is benzoic acid in an amount of 0.5% to        1.5%, e.g., 1%, and the non-aqueous orally-acceptable solvent is        propylene glycol, in an amount of 5% to 20%;    -   in step b), the amount of flavor components is 20% to 35%; and    -   in step c), the solid binder is microcrystalline cellulose in        the amount of 55% to 60% and a salt is present which is        potassium chloride in the amount of 1% to 1.5%;    -   wherein all amounts are given by weight of the product of step        c).

1.36. The foregoing method wherein the weight percent of themicrocrystalline cellulose plus the potassium fluoride is 55% to 65% andthe weight percent of the propylene glycol plus the flavor is 35% to40%.

1.37. Any foregoing method wherein in step d), each pouch is filled witha mixture of the product of step c) containing 1 mg to 10 mg nicotine(weight given as free base equivalent).

1.38. Any foregoing method, wherein the product is any of Formula 1, etseq.

In a further embodiment, the disclosure provides a method of deliveringnicotine to a subject comprising administering a chewable nicotineformulation according to any of Formulation 1, et. seq. to the subject,e.g., a needed, e.g., up to 3× daily, e.g., wherein the subject is apatient in need of nicotine replacement therapy.

Example 1: Nicotine Pouch Formulations

Formulation A—

The following components are combined as described above:

Name of Material Absolute Quantity(% w/w) Nicotine 2.00% Benzoic acid2.00% Propylene glycol 14.40%  Flavor Mix 21.60%  MCC 58.84%  PotassiumChloride 1.16% Total  100%

The propylene glycol is heated in a heated mixing tank to 70° C. Benzoicacid is added and mixed until it completely dissolves. Then nicotine isadded and mixed well. Flavor components are added one by one and mixedto form a liquid premix. Microcrystalline cellulose (MCC) and potassiumchloride are mixed in a ribbon blender, then the liquid premix mixtureis added to the microcrystalline cellulose (MCC) and potassium chloridein the ribbon blender and all ingredients are mixed well, to form apowder. The powder is then measured to provide the desired dose ofnicotine and placed in pouches.

Formulation B—

The following components are combined as described above:

Name of Material Absolute Quantity(% w/w) Nicotine 2.00% Benzoic acid2.00% Propylene glycol 4.00% Flavor Mix 32.00%  MCC 58.84%  PotassiumChloride 1.16% Total  100%

Formulation C—

The following components are combined:

Name of Material Absolute Quantity(% w/w) Nicotine 2.00% Benzoic acid1.00% Propylene glycol 5.00% Flavor Mix 32.00%  MCC 58.84%  PotassiumChloride 1.16% Total  100%

Formulation D—

The following components are combined as described above:

Name of Material Absolute Quantity(% w/w) Nicotine 2.00% Benzoic acid1.00% Propylene glycol 15.40%  Flavor Mix 21.60%  MCC 58.84%  PotassiumChloride 1.16% Total  100%

Formulation E—

The following components are combined as described above:

Name of Material Absolute Quantity(% w/w) Nicotine 2.00% Benzoic acid1.00% Propylene glycol 15.40%  Flavor Mix 21.60%  MCC  60% Total  100%

Formulation F—

The following components are combined as described above:

Name of Material Absolute Quantity(% w/w) Nicotine 2.00% Benzoic acid1.00% Propylene glycol 5.00% Flavor Mix 32.00%  MCC  60% Total  100%

Example 2: Nicotine Pouch Formulation Performance

The liquid premixes for Formulations C, D, E and F have an apparent pHof about 6.5, while the liquid premixes for Formulations A and B have anapparent pH of about 5.5, when measured using a standard pH sensor(i.e., a pH-sensitive glass electrode concentrically surrounded by areference electrode filled with reference electrolyte, which measuresthe H⁺ ion concentration of a solution). Note that while thismeasurement is not a true pH, as the liquid premixes are non-aqueous, itprovides a useful measure of comparative proton activity.

Formulations A and B, having higher levels of benzoic acid, are testedand found to have inferior mouth feel relative to Formulations C and D.Formulations C and D provide a “tingling” sensation, which is preferredby users.

Formulations C and D, which have potassium chloride, are found toprovide a fresher, cleaner taste compared to Formulations E and F, whichdo not contain potassium chloride.

Various solvents are tested, including other alcohols. Propylene glycolis preferred over other solvents, as it is found to dissolve both theacid and the nicotine efficiently and without excessive heating, whichis important, as heating can cause the nicotine to volatilize and cangenerate toxic fumes.

1.-17. (canceled)
 18. A method of making a chewable nicotine pouchformulation comprising nicotine free base, an orally-acceptable nicotinesalt, propylene glycol, flavor components, and an orally-acceptablebinder in a water-permeable, water-insoluble pouch, wherein the chewablenicotine formulation is substantially free of tobacco material,comprising the steps of a) dissolving nicotine and an orally-acceptableacid in the propylene glycol, b) adding the flavor components, c) mixingwith the orally-acceptable binder and optionally a salt, and d) fillingthe water-permeable, water-insoluble pouch with the mixture thusobtained.
 19. A method of delivering nicotine to a subject comprisingadministering to the subject a nicotine pouch formulation comprisingnicotine free base, an orally-acceptable nicotine salt, propyleneglycol, flavor components, and an orally-acceptable binder in awater-permeable, water-insoluble pouch, wherein the chewable nicotineformulation is substantially free of tobacco material, wherein theorally-acceptable nicotine salt is prepared by dissolving nicotine freebase and an orally-acceptable acid in the propylene glycol, and furtherwherein the subject is a patient in need of nicotine replacementtherapy.
 20. The method of claim 19, wherein the orally-acceptablenicotine salt is nicotine benzoate.
 21. The method of claim 19, whereinthe molar ratio between nicotine free base and orally-acceptablenicotine salt is about 1:2.
 22. The method of claim 19, wherein thebinder comprises microcrystalline cellulose.
 23. The method of claim 19,wherein the formulation further comprising a neutral, orally-acceptablemineral salt.
 24. The method of claim 19, wherein the formulation issubstantially free of any basic ingredient other than nicotine.
 25. Themethod of claim 19, wherein the formulation is made under substantiallywater-free conditions.
 26. The method of claim 19, wherein the contentsof the water-permeable, water-insoluble pouch have a pH of less than 7,when measured in a 10% slurry in water.
 27. The method of claim 19,wherein the ratio by weight of (i) binder and (if present) neutralorally-acceptable mineral salt, to (ii) nicotine, orally-acceptablenicotine salt, propylene glycol, and flavor, is from 70:30 to 50:50. 28.The method of claim 19, wherein the orally-acceptable nicotine salt isnicotine benzoate and the orally-acceptable binder is microcrystallinecellulose.
 29. The method of claim 19, wherein the contents of thewater-permeable, water-insoluble pouch are in dry powder form.
 30. Themethod of claim 19, wherein the formulation comprises 1%-9% of nicotineand orally-acceptable nicotine salts; 4% to 20% of propylene glycol;50%-70% of binder; 0.5%-2% of orally-acceptable mineral salt, whereinall percentages are by weight of the contents of the water-permeable,water-insoluble pouch.
 31. The method of claim 19, wherein the contentsof the water-permeable, water-insoluble pouch comprise: a) Nicotine: 1%to 6%